Suppression of the cup-5 mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter in C-elegans
Suppression of the cup-5 mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter in C-elegans
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DOI：
10.1242/dev.02575
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发表时间：
2006-10-01
期刊：
影响因子：
4.6
通讯作者：
Fares, Hanna
中科院分区：
文献类型：
--
作者：
Schaheen, Lara;Patton, Greg;Fares, Hanna
MCOLN 1（编码蛋白质粘脂1）的突变导致溶酶体贮积病粘脂沉积症IV型。对人类粘脂1和CUP-5（粘脂1的秀丽隐杆线虫直系同源物）的研究表明，这些蛋白质是溶酶体生物发生/功能所需的。CUP-5的缺失导致溶酶体降解缺陷，导致胚胎死亡。我们已经确定了ABC转运蛋白MRP-4中的突变，该突变由于CUP-5的缺失而挽救了降解缺陷和相应的致死性。MRP-4定位于内吞区室，并且其水平在不存在CUP-5的情况下升高。这些结果表明，由于MRP- 4在溶酶体中的积累而不是CUP-5本身的损失，溶酶体降解缺陷在一些细胞中加剧。我们还表明，在某些条件下，MRP- 4的损失挽救了胚胎的组织蛋白酶L蛋白酶的损失所造成的死亡率，表明ABC转运蛋白的积累可能是一个更普遍的机制，从而初始溶酶体功能障碍是更严重的妥协。
Mutations in MCOLN1, which encodes the protein mucolipin 1, result in the lysosomal storage disease mucolipidosis Type IV. Studies on human mucolipin 1 and on CUP-5, the Caenorhabditis elegans ortholog of mucolipin 1, have shown that these proteins are required for lysosome biogenesis/function. Loss of CUP-5 results in a defect in lysosomal degradation, leading to embryonic lethality. We have identified a mutation in the ABC transporter MRP-4 that rescues the degradation defect and the corresponding lethality, owing to the absence of CUP-5. MRP-4 localizes to endocytic compartments and its levels are elevated in the absence of CUP-5. These results indicate that the lysosomal degradation defect is exacerbated in some cells because of the accumulation of MRP- 4 in lysosomes rather than the loss of CUP-5 per se. We also show that under some conditions, loss of MRP- 4 rescues the embryonic lethality caused by the loss of the cathepsin L protease, indicating that the accumulation of ABC transporters may be a more general mechanism whereby an initial lysosomal dysfunction is more severely compromised.